A Rac-specific competitive inhibitor of guanine nucleotide binding reduces metastasis in triple-negative breast cancer

Publié le 8 juillet 2025 - Cell Reports Medicine

Auteurs : Florian Dilasser, Lindsay Rose, Agnès Quemener, Yann Ferrandez, Dorian Hassoun, Morgane Rousselle, Hugo Bergereau, Séverine Marionneau Lambot, Luciano E Anselmino, Camille Trouillet, Gwennan Andre, Mike Maillasson, Mikael Croyal, Matthieu Riviere, Didier Dubreuil, Sylvain Collet, Frédérique Souaze, Mario Campone, Anne Patsouris, Erwan Mortier, Mauricio Menacho Marquez, Philippe Juin, Jacques Lebreton, Arnaud Tessier, Jacqueline Cherfils, Gervaise Loirand, Vincent Sauzeau

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• A41 is a specific and reversible inhibitor of RAC proteins • A41 competes with guanine nucleotide binding • A41 blocks RAC1 activity and RAC1-dependent cell functions in cancer cells • A41 exhibits anti-metastatic effects and increase of the survival rate The dysregulation of RAC1 activity is associated with neoplastic transformation, metastasis, and poor prognosis in several cancers. Here, we discover in silico a series of RAC1 inhibitors. The most potent of them, A41, specifically inhibits RAC1 with an original mechanism of action. We characterize A41 as a reversible inhibitor that competes with guanine nucleotide binding specifically on RAC proteins. A41 efficiently blocks RAC1 activity and RAC1-dependent cell functions including cell adhesion and migration. Chronic administration of A41 exhibits anti-metastatic effects in mouse models of triple-negative breast cancer, leading to an increase in the survival rate. Our findings suggest that this molecule, A41, could be a promising and powerful therapeutic agent for limiting invasive cancers in patients.